Prodrugs of sulfasalazine, pharmaceutical compositions thereof and their use in the treatment of autoimmune disease

Abstract

The present invention relates to new compounds of formula I and pharmaceutically acceptable salts and/or co-crystals thereof. The present invention also relates to pharmaceutical compositions comprising these compounds and to their use as medicaments for the prevention, prophylaxis of progression, and/or treatment of a disease in which modulation of extracellular (chemotactic) cytokines and/or TNF-alpha and or nuclear factor kappa B (NFKB) and/or inflammatory cells is beneficial, such as autoimmune diseases, like rheumatoid arthritis, oligoarthritis, spondyloarthropathy, psoriatic arthritis, psoriasis and inflammatory bowel diseases, such as Crohns' disease and ulcerative colitis.

The invention claimed is:   
     
       1. A compound of formula I, a pharmaceutically acceptable salt, crystals and/or co-crystal thereof, diastereomer, enantiomer, or mixture thereof, wherein: 
       
         
           
           
               
               
           
         
         R 1  and R 2  are independently chosen from hydrogen and C 1-6 alkyl, R 3  and R 4  are independently chosen from hydrogen, C 1-6 alkyl, C 1-6 heteroalkyl, C 3-12 cycloalkyl, C 3-12 heterocycloalkyl, C 5-13 aryl, C 5-13 heteroraryl, C 3-12 cycloalkylC 1-6 alkyl, C 3-12 heterocycloalkylC 1-6 alkyl, C 5-13 arylC 1-6 alkyl and C 5-13 heteroarylC 1-6 alkyl, or R 3  and R 4  together with the nitrogen to which they are attached form a ring chosen from C 3-12 heterocycloalkyl and C 5-13 heteroaryl, and wherein R 1 , R 2 , R 3  and R 4  are optionally substituted with one or more R, and R is independently chosen from halogen, —OH, —SH, —CN, —CF 3 , ═O, —NO 2 , —C(O)NR 5 R 6 , —R 5 , —OR 5 , —SR 5 , —C(O)R 5 , —COOR 5  and —NR 5 R 6 , wherein R 5  and R 6  are independently chosen from hydrogen, C 1-4 alkyl and C 1-4 cycloalkyl, and optionally substituted with one or more R 7 , wherein R 7  is chosen from halogen, —OH, —SH, —CN, —CF 3 , ═O, —NO 2 , —C(O)NR 8 R 9 , —R 8 , —OR 8 , —SR 8 , —C(O)R 8 , —COOR 8  and —NR 8 R 9 , wherein R 8  and R 9  are independently chosen from hydrogen, C 1-4 alkyl and C 1-4 cycloalkyl. 
       
     
     
       2. The compound according to  claim 1 , wherein R 1  and R 2  are hydrogen, R 3  and R 4  are independently chosen from hydrogen, C 1-4 alkyl, C 1-4 heteroalkyl, C 3-7 cycloalkyl, C 3-7 heterocycloalkyl, C 5-6 aryl, C 5-6 heteroraryl, C 3-6 cycloalkylC 1-4 alkyl, C 3-6 heterocycloalkylC 1-4 alkyl, C 5-6 arylC 1-4 alkyl and C 5-6 heteroarylC 1-4 alkyl, or R 3  and R 4  together with the nitrogen to which they are attached form a ring chosen from C 3-8 heterocycloalkyl and C 5-6 heteroaryl, and wherein R 1 , R 2 , R 3  and R 4  are optionally substituted with one or more R. R is independently chosen from halogen, —OH, —SH, —CN, —CF 3 , ═O, —NO 2 , —C(O)NR 5 R 6 , —R 5 , —OR 5 , —SR 5 , —C(O)R 5 , —COOR 5  and —NR 5 R 6 , wherein R 5  and R 6  are independently chosen from hydrogen, C 1-4 alkyl and C 1-4 cycloalkyl, and optionally substituted with one or more R 7 , wherein R 7  is chosen from halogen, —OH, —SH, —CN, —CF 3 , ═O, —NO 2 , —C(O)NR 8 R 9 , —R 8 , —OR 8 , —SR 8 , —C(O)R 8 , —COOR 8  and —NR 8 R 9 , wherein R 8  and R 9  are independently chosen from hydrogen, C 1-4 alkyl and C 1-4 cycloalkyl. 
     
     
       3. The compound according to  claim 2 , wherein R 1  and R 2  are hydrogen, R 3  and R 4  are independently chosen from hydrogen, C 1-6 alkyl, C 3-12 cycloalkyl, C 3-12 cycloalkylC 1-6 alkyl, or R 3  and R 4  together with the nitrogen to which they are attached form a ring chosen from C 3-12 heterocycloalkyl; and wherein R 3  and R 4  are optionally substituted with one or more R, and R is —OR 5  or R 5  wherein R 5  is C 1-4 alkyl. 
     
     
       4. The compound according to  claim 2 , wherein R 1 , R 2  and R 3  are hydrogen. 
     
     
       5. The compound according to  claim 2 , wherein R 1 , R 2  and R 3  are hydrogen and R 4  is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 2-hydroxyethyl, 2-methoxyethyl, cyclopentyl or cyclopropylmethyl. 
     
     
       6. A compound or a pharmaceutically acceptable salt, crystals or co-crystal thereof, selected from the group comprising
 2-morpholino-2-oxoethyl-(E)-2-hydroxy-5-((4-(N-(pyridine-2-yl) sulfamoyl)phenyl)diazenyl)benzoate, 
 2-(3-methyl-azetidinyl)-2-oxoethyl-2-hydroxy-5-((4-(N-(pyridine-2-yl)sulfamoyl)phenyl) diazenyl)benzoate, 
 2-azetidinyl-2-oxoethyl-2-hydroxy-5-((4-(N-(pyridine-2-yl)sulfamoyl)phenyl)diazenyl) benzoate, 
 2-pyrrolidinyl-2-oxoethyl-2-hydroxy-5-((4-(N-(pyridine-2-yl) sulfamoyl)phenyl)diazenyl) benzoate, 
 2-piperidinyl-2-oxoethyl-2-hydroxy-5-((4-(N-(pyridine-2-yl)sulfamoyl)phenyl)diazenyl) benzoate, 
 2-piperazinyl-2-oxoethyl-2-hydroxy-5-((4-(N-(pyridine-2-yl)sulfamoyl)phenyl)diazenyl) benzoate, and 
 2-azepanyl-2-oxoethyl-2-hydroxy-5-((4-(N-(pyridine-2-yl) sulfamoyl)phenyl)diazenyl) benzoate. 
 
     
     
       7. A compound or a pharmaceutically acceptable salt, crystals or co-crystal thereof, selected from
 2-(ethylamino)-2-oxoethyl-2-hydroxy-5-((4-(N-(pyridine-2-yl)sulfamoyl)phenyl)diazenyl) benzoate, 
 2-(isobutylamino)-2-oxoethyl-2-hydroxy-5-((4-(N-(pyridine-2-yl) sulfamoyl)phenyl)diazenyl) benzoate, 
 2-(cyclopentylamino)-2-oxoethyl-2-hydroxy-5-((4-(N-(pyridine-2-yl)sulfamoyl)phenyl) diazenyl)benzoate, 
 2-(methylamino)-2-oxoethyl-2-hydroxy-5-((4-(N-(pyridine-2-yl) sulfamoyl)phenyl) diazenyl)benzoate, 
 2-(isopropylamino)-2-oxoethyl-2-hydroxy-5-((4-(N-(pyridine-2-yl)sulfamoyl)phenyl)diazenyl) benzoate, 
 2-((cyclopropylmethyl)amino)-2-oxoethyl-2-hydroxy-5-((4-(N-(pyridine-2-yl)sulfamoyl) phenyl)diazenyl)benzoate, 
 2-(propylamino)-2-oxoethyl-2-hydroxy-5-((4-(N-(pyridine-2-yl) sulfamoyl)phenyl)diazenyl)benzoate, 
 2-((2-methoxylethyl)amino)-2-oxoethyl-2-hydroxy-5-((4-(N-(pyridine-2-yl)sulfamoyl)phenyl)diazenyl) benzoate, 
 2-(dimethylamino)-2-oxoethyl-2-hydroxy-5-((4-(N-(pyridine-2-yl)sulfamoyl)phenyl)diazenyl) benzoate, 
 2-(diethylamino)-2-oxoethyl-2-hydroxy-5-((4-(N-(pyridine-2-yl) sulfamoyl)phenyl)diazenyl) benzoate, 
 2-(dipropylamino)-2-oxoethyl-2-hydroxy-5-((4-(N-(pyridine-2-yl) sulfamoyl)phenyl)diazenyl) benzoate, 
 2-(dibutylamino)-2-oxoethyl-2-hydroxy-5-((4-(N-(pyridine-2-yl) sulfamoyl)phenyl)diazenyl) benzoate, and 
 2-(di-(1-methylethylamino))-2-oxoethyl-2-hydroxy-5-((4-(N-(pyridine-2-yl) sulfamoyl)phenyl) diazenyl)benzoate. 
 
     
     
       8. A compound, or a pharmaceutically acceptable salt or co-crystal thereof, selected from
 N-ethyl-N-methylamino-2-oxoethyl-2-hydroxy-5-((4-(N-(pyridine-2-yl)sulfamoyl)phenyl) diazenyl)benzoate, 
 N-methyl-N-2-methylethylamino-2-oxoethyl-2-hydroxy-5-((4-(N-(pyridine-2-yl)sulfamoyl)phenyl)diazenyl)benzoate, 
 N-butyl-N-methylamino)-2-oxoethyl-2-hydroxy-5-((4-(N-(pyridine-2-yl) sulfamoyl)phenyl) diazenyl)benzoate, 
 N-methyl-N-(2,2-dimethylpropyl)amino-2-oxoethyl-2-hydroxy-5-((4-(N-(pyridine-2-yl)sulfamoyl)phenyl)diazenyl)benzoate, 
 N-butyl-N-ethylamino-2-oxoethyl-2-hydroxy-5-((4-(N-(pyridine-2-yl) sulfamoyl)phenyl) diazenyl)benzoate, 
 N-cyclohexyl-N-methylamino-2-oxoethyl-2-hydroxy-5-((4-(N-(pyridine-2-yl) sulfamoyl)phenyl) diazenyl)benzoate, 
 N-ethyl-N-cyclohexylamino-2-oxoethyl-2-hydroxy-5-((4-(N-(pyridine-2-yl) sulfamoyl)phenyl) diazenyl)benzoate, and 
 N-(2-(methylethyl)-N-(2,2-dimethylpropyl)amino-2-oxoethyl-2-hydroxy-5-((4-(N-(pyridine-2-yl)sulfamoyl)phenyl)diazenyl)benzoate. 
 
     
     
       9. The compound according to  claim 1 , wherein the ratio of C SS , C max  and/or AUC of sulfapyridine to sulfasalazine in blood plasma after oral administration to a subject of the compound, compared to said ratio after oral administration of sulfasalazine to the subject, is decreased at least by a factor of 1.5. 
     
     
       10. A pharmaceutical composition comprising the compound according to  claim 1  or a pharmaceutically acceptable salt or co-crystal thereof, in association with a pharmaceutically acceptable adjuvant, diluent or carrier. 
     
     
       11. A pharmaceutical composition comprising (i) a compound of  claim 1 , (ii) an additional therapeutic agent, or a pharmaceutically acceptable salt thereof, and (iii) one or more pharmaceutically acceptable excipient, carrier or diluent. 
     
     
       12. A pharmaceutical composition comprising (i) a compound of  claim 1 , together with a pharmaceutically acceptable excipient, carrier or diluent (ii) an additional therapeutic agent, or a pharmaceutically acceptable salt thereof, together with a second pharmaceutically acceptable excipient, carrier or diluent. 
     
     
       13. The pharmaceutical composition according to  claim 11 , wherein at least one agent is selected from the group consisting of methotrexate, sulfasalazine and hydroxychloroquine, or a pharmaceutically acceptable salt thereof. 
     
     
       14. The pharmaceutical composition according to  claim 11 , wherein at least one agent is selected from the group consisting of infliximab, adalimumab, certolizumab, etanercept, golimumab, tocilizumab, rituximab, abatacept, anakinra, secukinumab, ixekizumab or ustekinumab. 
     
     
       15. A process for the preparation of a compound of  claim 1 , the process comprising the steps of:
 (i) mixing sulfasalazine and 1.0 to 1.5 equivalent of base in an organic solvent under stirring for 0.5 to 4 h at a temperature between 15 and 60° C., 
 (ii) adding 1.0 to 1.5 equivalent of halo-acetamide in an organic solvent under stirring for 10 to 48 h at a temperature between 60 to 130° C., optionally in the presence of KI, 
 (iii) cooling and partition between an aqueous saturated NaCl solution and organic solvent, drying the organic solvent using an anhydrous MgSO 4  or Na 2 SO 4  or similar, filtrating and evaporating the solvent, and 
 purifying using chromatography and/or crystallization. 
 
     
     
       16. A method of preventing, delaying progression or treating an autoimmune disease in a subject comprising administering to the subject a compound of  claim 1 . 
     
     
       17. A method of preventing, delaying progression or treating an arthritis in a subject comprising administering to the subject a compound of  claim 1 , wherein the arthritis is selected from rheumatoid arthritis and the active juvenile idiopathic form thereof, Stills' disease, oligoarthritis and the active juvenile idiopathic form thereof, polyarthritis and the active juvenile idiopathic form thereof, seronegative spondyloarthropathies including ankylosing spondylitis, spondyloarthropathy with peripheral arthritis, axial spondyloarthritis and the active juvenile idiopathic forms thereof. 
     
     
       18. A method of preventing, delaying the progression or treating an inflammatory bowel disease in a subject comprising administering to the subject a compound of  claim 1 . 
     
     
       19. The method of  claim 18 , wherein the inflammatory bowel disease is selected from eosinophilic gastro-enteritis, mastocytosis, Crohn's disease, colitis including ulcerative colitis, proctitis, coeliac disease, irritable bowel syndrome, and food-related allergies, which may have effects remote from the gut, such as migraine, rhinitis or eczema, including juvenile idiopathic forms thereof. 
     
     
       20. A method of modulating an autoinflammatory response in a subject comprising administering to the subject a composition of  claim 10 .